Pharmacokinetics of tocainide in patients with renal dysfunction and during haemodialysis.

The disposition of tocainide was studied in 15 patients with renal dysfunction. In 9 with total renal failure, the plasma half-life ranged from 16.6 to 42.7 h and total plasma clearance from 35 to 94 ml/min. The longest half-lives were found in 1 patient with cirrhosis, 3 taking the enzyme inhibitor allopurinol, and 1 on cimetidine. The mean half-life in the remaining patients was 22.3 +/- 4.8 h (+/- SD). During a 4 h haemodialysis, the half-life in the 9 patients decreased to 8.5 +/- 4.6 h, which was calculated to correspond to removal of 25 +/- 14% of the drug from the body. In 6 patients with impaired renal function (creatinine clearance 10-55 ml/min) the tocainide half-life ranged from 13.2 to 22.0 h and total plasma clearance from 72 to 122 ml/min. One patient was taking allopurinol and 1 dihydralazine, and the mean half-life in the others was 19.2 +/- 4.0 h. The apparent volume of distribution was similar to that found previously in healthy subjects. The results suggest that tocainide elimination is predictably reduced in patients with renal disease.

[Amino acid kinetics during hemodialysis]. / Kinetik von Aminosäuren während Hämodialyse.

The kinetic of essential amino acids as well as of histidine and alanine in bilateral nephrectomized rabbits was investigated during a 3 hours hemodialysis. Dialysis, elimination and incorporation rates into plasma proteins were determined for all applied amino acids. Total elimination rates of all the investigated amino acids varied. From 5.31% (leucine) to 75.51% (alanine) of the injected labelled amino acids were eliminated in the dialysate. There was an exponential decrease in the dialysis of essential amino acids and histidine during the period of investigation due to the high incorporation rate into plasma proteins. The kinetic of alanine was different due to a slow incorporation rate leading to a higher elimination rate. The fast incorporation of intravenously applied essential amino acids and histidine during dialysis demonstrates that the existing protein deficiency in renal failure can be influenced positively by infusion of amino acids.

Altered metabolism of phospholipids in the lung of rats with peritonitis.

Pulmonary alterations after shock and sepsis, described clinically as shock lung or adult respiratory distress syndrome, are of great importance in intensive care. Pathogenetically an alteration of the surfactant system of the lung is often discussed. Since phospholipids are constituents of lung surfactants, phospholipid metabolism is investigated in experimental peritonitis in rats in our laboratory. 15 hours after inducing a peritonitis, the lung incorporates more oleic acid than that in animals of the reference group. 33 hours after inducing peritonitis, the capacity of the lung to incorporate choline and fatty acids is markedly reduced, histologically the lungs represent morphological equivalents of the so-called shock lung at this time. Therefore we conclude, that an alteration of phospholipid metabolism with a diminished and/or altered synthesis of lung surfactant plays, at least in part, an important role in the pathogenesis of respiratory distress in sepsis and peritonitis.

A kinetic study of lung DNA-synthesis during simulated chronic high altitude hypoxia.

Rats were exposed to crhonic hypobaric hypoxia at a simulated altitude of 4250 m for 3, 6, 9, 12, 20, and 35 days. The in-vitro incorporation of 3H-thymidine into the DNA of lung tissue was measured and compared with that of normoxic controls: the obtained time course study showed a maximum increase of 345% on the ninth day of hypoxia, indicating a marked stimulation of cellular proliferation. Between the 12th and 20th day of hypoxia, the lung DNA-synthesis reached control values. No significant change in the DNA-concentration of the lungs was registered. The response to hypoxia was less impressive in rat livers used as controls.

Increased incorporation of fatty acids into phospholipids of lungs and livers of rabbits under the influence of bromhexine and ambroxol.

The incorporation of lauric acid, palmitic acid and oleic acid into phospholipids of lung and liver has been studied in tissue slices of control rabbits and of rabbits treated with bromhexine or ambroxol in doses of 10 mg/kg. A marked increase (up to 200% of the controls) of palmitic acid incorporation into phosphatidylcholine (lecithin) and phosphatidylethanolamine of the lung was found whereas the incorporation rate of palmitic acid into lecithin and phosphatidylethanolamine of the liver displayed no significant change. The incorporation of lauric acid and oleic acid into lung phospholipids was not accelerated. The observed effects were more marked in short time experiments (analysis 2 h after drug injection) than after treatements for 7 days. It is concluded that the phospholipid synthesis is stimulated by the drugs especially in the lungs. This seems to be of particular interest with respect to the surfactant system of the lung and might have some therapeutic relevance.

Separate pyrimidine-nucleotide pools for messenger-RNA and ribosomal-RNA synthesis in HeLa S3 cells.

Kinetic analyses of mRNA and 28-S RNA labeling [3H]uridine revealed distinctly different steady-state specific radioactivities finally reached for uridine in mRNA and 28-S RNA when exogenous [3H]uridine was kept constant for several cell doubling times. While the steady-state label of (total) UTP and of uridine in mRNA responded to the same extent to a suppression of pyrimidine synthesis de novo by high uridine concentrations in the culture medium, uridine in 28-S RNA was scarcely influenced. Similar findings were obtained with respect to labeling of cytidine in the various RNA species due to an equilibration of UTP with CTP [5-3H]Uridine is also incorporated into deoxycytidine of DNA, presumably via dCTP. The specific radioactivity of this nucleosidase attained the same steady-state value as UTP, uridine in mRNA and cytidine in mRNA. The data indicate the existence of two pyrimidine nucleotide pools. One is a large, general UTP pool comprising the bulk of the cellular UTP and serving nucleoplasmic nucleic acid formation (uridine and cytidine in mRNA, deoxycytidine in DNA). Its replenishment by de novo synthesis can be suppressed completely by exogenous uridine above 100 muM concentrations. A second, very small UTP (and CTP) pool with a high turnover provides most of the precursors for nucleolar RNA formation (rRNA). This pool is not subject to feedback inhibition by extracellular uridine to an appreciable extent. Determinations of (total) UTP turnover also show that the bulk of cellular RNA (rRNA) cannot be derived from the large UTP pool.

Stimulation of proteinase K action by denaturing agents: application to the isolation of nucleic acids and the degradation of 'masked' proteins.

Hydrolysis of serum albumin by proteinase K was strongly (greater than 7-fold) stimulated by urea and dodecylsulfate in a dose-dependent manner. With an oligopeptide as substrate, however, proteinase K was inactivated by dodecylsulfate. This indicates that the apparent activation of proteinase K by urea and dodecylsulfate is caused primarily by denaturation of the protein substrates. Although dodecylsulfate inhibited ribonuclease activity in the test-tube completely, it could not prevent RNA degradation during isolation of polysomal RNA, to which ribonuclease had been added, because of the reversible nature of the dodecylsulfate inhibition. Complete protection of RNA, however, was achieved by a combination of dodecylsulfate and proteinase K. The combined action of the detergent and proteinase K was also effective in degrading "masked" proteins in a poly(adenosine diphosphoribose) preparation which could not be attacked by the proteinase alone.

Determination of mRNA half-life in HeLa cultures by a poly(A)-independent direct analysis of specific radioactivity of mRNA.

mRNA specific radioactivity in HeLa cultures exposed to (3H)uridine (10 muM) was determined directly by a highly selective poly(A)-independent method which we have described previously. Neither uridine in mRNA nor UTP approached the specific radioactivity of the exogenous (3H)uridine, but attained steady-state specific radioactivities which remained a third below the value of the added precursor. Using the labeling data for the evaluation of mRNA turnover, previously described by Greenberg, mRNA half-life in exponentially growing HeLa cultures was found to be 0.87 times the cell doubling time. Decay curves of mRNA in prelabeled cultures were in accordance with these values (half-life equals 0.79 times the cell doubling time) when corrected for growth and also for "reutilization" which was accomplished by relating uridine labeling in mRNA to UTP specific radioactivity. The experiments showed that an exact evaluation of mRNA turnover is possible only when the following points are taken into account. a) A constant supply of exogenous labeled uridine must be provided to guarantee a constant specific radioactivity of UTP. b) Labeling of CTP and of cytidine in RNA are delayed when compared with UTP and uridine in RNA. Corrections for cytidine labeling in RNA are therefore required. c) As rRNA approached a definitely lower steady-state specific radioactivity than mRNA, mRNA specific radioactivities must be determined directly (i.e. by radioactivity and absorbance at 260 nm in isolated mRNA fractions) in order to evaluate true turnover of this RNA species.